Antidepressant treatments and function of glutamate ionotropic receptors mediating amine release in hippocampus.

Previous evidences showed that, besides noradrenaline (NA) and 5-hydroxytryptamine (5-HT), glutamate transmission is involved in the mechanism of action of antidepressants (ADs), although the relations between aminergic and glutamatergic systems are poorly understood. The aims of this investigation were to evaluate changes in the function of glutamate AMPA and NMDA receptors produced by acute and chronic administration of the two ADs reboxetine and fluoxetine, selective inhibitors of NA and 5-HT uptake, respectively. Rats were treated acutely (intraperitoneal injection) or chronically (osmotic minipump infusion) with reboxetine or fluoxetine. Isolated hippocampal nerve endings (synaptosomes) prepared following acute/chronic treatments were labelled with [(3)H]NA or [(3)H]5-HT and [(3)H]amine release was monitored during exposure in superfusion to NMDA/glycine, AMPA or K(+)-depolarization. Acute and chronic reboxetine reduced the release of [(3)H]NA evoked by NMDA/glycine or by AMPA. The NMDA/glycine-evoked release of [(3)H]NA was also down-regulated by chronic fluoxetine. Only acute, but not chronic, fluoxetine inhibited the AMPA-evoked release of [(3)H]5-HT. The release of [(3)H]NA and [(3)H]5-HT elicited by K(+)-depolarization was almost abolished by acute reboxetine or fluoxetine, respectively, but recovered during chronic ADs administration. ADs reduced NMDA receptor-mediated releasing effects in noradrenergic terminals after acute and chronic administration, although by different mechanisms. Chronic treatments markedly reduced the expression level of NR1 subunit in synaptic membranes. The noradrenergic and serotonergic release systems seem to be partly functionally interconnected and interact with glutamatergic transmission to down-regulate its function. The results obtained support the view that glutamate plays a major role in AD activity.

Long-term soluble Abeta1-40 activates CaM kinase II in organotypic hippocampal cultures.

Recent findings suggested a role for soluble amyloid-beta (Abeta) peptides in Alzheimer's disease associated cognitive decline. We investigated the action of soluble, monomeric Abeta(1-40) on CaM kinase II, a kinase involved in neuroplasticity and cognition. We treated organotypic hippocampal cultures short-term (up to 4h) and long-term (5 days) with Abeta(1-40) (1nM-5microM). Abeta did not induce cell damage, apoptosis or synaptic loss. Short-term treatment down-regulated enzymatic activity of the kinase, by reducing its Thr(286) phosphorylation. In contrast, long-term treatment (1nM-microM) markedly and significantly up-regulated enzymatic activity, with peak stimulation at 10nM (three-fold). Up-regulation of activity was associated with increased expression of the alpha-isoform of CaM kinase II, increased phosphorylation at Thr(286) (activator residue) and decreased phosphorylation at Thr(305-306) (inhibitory residues). We investigated the effect of glutamate on CaM kinase II following exposure to 1 or 10nM Abeta(1-40). As previously reported, glutamate increased CaM kinase II activity. However, the glutamate effect was not altered by pretreatment of slices with Abeta. Short- and long-term Abeta treatment showed opposite effects on CaM kinase II, suggesting that long-term changes are an adaptation to the kinase early down-regulation. The marked effect of Abeta(1-40) on the kinase suggests that semi-physiological and slowly raising peptide concentrations may have a significant impact on synaptic plasticity in the absence of synaptic loss or neuronal cell death.